title: Enu mutagenesis identifies a novel platelet phenotype in a loss-of-function Jak2 allele.
abstract: Utilizing ENU mutagenesis, we identified a mutant mouse with elevated platelets. Genetic mapping localized the mutation to an interval on chromosome 19 that encodes the Jak2 tyrosine kinase. We identified a A3056T mutation resulting in a premature stop codon within exon 19 of Jak2 (Jak2(K915X)), resulting in a protein truncation and functionally inactive enzyme. This novel platelet phenotype was also observed in mice bearing a hemizygous targeted disruption of the Jak2 locus (Jak2(+/-)). Timed pregnancy experiments revealed that Jak2(K915X/K915X) and Jak2(-/-) displayed embryonic lethality; however, Jak2(K915X/K915X) embryos were viable an additional two days compared to Jak2(-/-) embryos. Our data suggest that perturbing JAK2 activation may have unexpected consequences in elevation of platelet number and correspondingly, important implications for treatment of hematological disorders with constitutive Jak2 activity.
authors.affiliation: Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Anderson
authors.forename: Mojib
authors.initials: M
authors.lastname: Javadi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Berndl
authors.forename: Zorana
authors.initials: Z
authors.lastname: Berberovic
authors.forename: Monica L
authors.initials: ML
authors.lastname: Bailey
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Ann M
authors.initials: AM
authors.lastname: Flenniken
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Osborne
authors.forename: S Lee
authors.initials: SL
authors.lastname: Adamson
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.forename: Christin
authors.initials: C
authors.lastname: Carter-Su
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McNagny
authors.forename: Robert F
authors.initials: RF
authors.lastname: Paulson
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: Dwayne L
authors.initials: DL
authors.lastname: Barber
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D015153:Blotting, Western; D002874:Chromosome Mapping; D005038:Ethylnitrosourea; D005472:Fluorouracil; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016296:Mutagenesis / Q000235:genetics; D010641:Phenotype; D010659:Phenylhydrazines; D017354:Point Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D010659:Phenylhydrazines; C030299:phenylhydrazine; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D005038:Ethylnitrosourea; D005472:Fluorouracil